Class II MHC (Ia) gene products play critical roles in a variety of T lymhocyte responses. A combination of immunological, molecular genetic, and biochemical approaches is being used to study the relationship between Ia structure function. Ia expression has been examined following transfer of class II genes into L cells. These experiments have shown that the efficiency of cell-surface Ia expression is controlled by both allele-specific and isotype-specific structural features of the alpha and beta chains. There are strong quantitative preferences in the formation and transport of certain heterodimers, explaining the phenotype of cells expressing multiple class II MHC alpha and beta chains. In vitro mutagenesis studies have mapped two major regions within the Ia molecule the play key roles in controlling the conformation of Ia molecules required for their transport to the cell membrane. Analysis of various recombinant Ia molecules with monoclonal antibodies has reveled an unexpected asymmetry in the conformational flexibility of the postulated alpha-helical regions of the polymorphic Ia domains. Site-directed mutagenesis studies have mapped the precise role of polymorphic residues of the I-E molecule with respect to T cell receptor interaction or peptide antigen binding. The cell biology of antigen processing and presentation by MHC molecules has been studied and a special role for the endosome/trans-Golgi low pH compartments demonstrated. The rules controlling class I vs class II MHC antigen presentation have been examined using artificially processed soluble protein antigens, with the data indicating that the way antigen enters a cell may determine the MHC molecule used for presentation to T cells. These studies are providing new insight into the rules governing T cell co-recognition of antigen and MHC molecules, and the biochemistry and cell biology of protein multimer synthesis and transport.